Process for preparing 4-substituted 1H-pyrrole-3-carboxylic acid ester

ABSTRACT

The present invention relates to a novel process for preparing pyrrole ester compounds, which are key intermediates in the preparation of farnesyl transferase inhibitors, an anti-cancer agent Horner-Emmons reaction of aldehyde compounds provides the corresponding α,β-unsaturated esters, which without any separation and/or purification steps, are treated with toluenesutfonyl-methylisocyanate in the presence of base to give pyrrole esters in one-pot fashion.

TECHNICAL FIELD

The present invention relates to a novel process for preparing pyrroleester compounds which are key intermediate in the preparation offarnesyl transferase inhibitors, an anti-cancer agent (see: Ko, J. S. etal., WO 9928315). Horner-Emmons reaction of aldehyde compounds providesthe corresponding α,β-unsaturated esters, which without any separationand/or purification steps, are treated withtoluenesulfonylmethylisocyanate (TosMIC: hereinafter referred to as‘TosMIC’) in the presence of base to give pyrrole esters in one-potfashion.

BACKGROUND ART

The most typical method for the synthesis of 3-substituted-4-pyrroleester compound is through the cyclization reaction of an isonitrilecompound with an electrophilic α,β-unsaturated compound, as depicted inthe following Reaction Scheme 1. As isonitrile part, TosMIC is the mostwell known reagent (van Leusen, A. M. et.al. Teiahedron Leit. 1972, 52,5337.).

in which

R₁ and R₂ independently of one another represent C₁-C₄-alkyl.

Recently BetMIC (Katrizky, A. R. et.al. Heterocycles, 1997, 44, 67.) ofthe following formula showing a similar reactivity to TosMIC has beendeveloped.

Thereafter, the same researcher has developed a new method as depictedin the following Reaction Scheme 2. TosMIC is reacted with a carbonylcompound in the presence of a base and POCl₃(phosphorous oxychloride) insequence to give an α,β-unsaturated isonitrile compound, which is thenreacted with an activated nucleophile to give a pyrrole compound (vanLeusen, A. M. et.al. J Org. Chem. 1992, 57, 2245.).

in which

R represents alkyl, allyl, or aryl, and

E represents an electron-withdrawing group.

As known in the previous arts, the general synthesis of3-substituted-4-pyrrole ester contains two discrete stages. The firststage is the preparation and purification of α,β-unsaturated compoundand the second stage is the cyclization reaction of the purifiedα,β-unsaturated compound with TosMIC in the presence of base. However,since the conventional method requires purification step after thepreparation of α,β-unsaturated compound, it is inevitable to efflux thereaction solvent as waste unless it is recycled. To remove the efflux ofwaste solvent and increase the efficiency of the process, it is proposedto run the two reactions in the same solvent as one-pot fashion.

DISCLOSURE OF INVENTION

Under the technical background as explained above, the present inventorshave investigated extensively on the eradication of the waste solventproblem and the increase of the efficiency of the process for thepurpose of mass production of pyrrole ester. As a result, we have comeup with the present invention by combining the two stages of the pyrrolesynthesis into one-pot/one stage process. Therefore, the pyrrole esteris obtained in high purity and in environmentally friendly manner.

The object of the present invention is to provide a process forpreparing a desired pyrrole ester derivative represented by thefollowing formula (1):

in which

R represents alkyl, allyl, or aryl, and

R¹ represents C₁-C₄-alkyl, by reacting an aldehyde compound representedby the following formula (2):

in which R is defined as previously described, with atrialkylphosphonoacetate represented by the following formula (3):

in which R¹ is defined as previously described, in an inert solvent inthe presence of an alkali metal alkoxide base in an amount of 1 to 1.5molar equivalent with respect to the compound of formula (2) to give anα,β-unsaturated ester compound represented by the following formula (4):

in which R and R¹ are defined as previously described, and subsequentlyby adding TosMIC and the same base as used in the previous step in anamount of 1 to 1.5 molar equivalent with respect to the compound offormula (2).

BEST MODE FOR CARRYING OUT THE INVENTION

The process according to the present invention is depicted in thefollowing Reaction Scheme 3

In the process of the present invention, it is very important to use thealkali metal alkoxide base in an amount of 1 to 1.5 molar equivalentswith respect to the compound of formula (2). If the amount of base isdeviated from the defined range, the reaction to prepare the unsaturatedester compound of formula (4) is not proceeded cleanly. As a result, theobject of the present invention to react the unsaturated ester compounddirectly in the next step in the same reaction system without beingseparated cannot be achieved. As the base which can be used for such apurpose, alkali metal methoxide, -ethoxide, -t-butoxide, -t-pentoxide,etc., preferably sodium- or potassium-t-butoxide or -t-pentoxide can beused. Though the reaction is well proceeded by using the base in anamount of 1 to 1.5 molar equivalents, however, 1 to 1.3 molar equivalentthereof may be sufficient to exhaust the aldehyde compound. Further, anexcess base may cause hydrolysis in the subsequent separation step oflayers, it is preferable to use the base in an amount of 1 to 1.3 molarequivalent in order to minimize such a hydrolysis reaction.

Any inert solvent which does not adversely affect to the reaction can beused in the process according to the present invention, buttetrahydrofuran, dimethoxyethane, toluene or mixtures thereof ispreferably used.

After the process for preparing the compound of formula (4) iscompleted, TosMIC and the same base as used in the previous reactionstep were added and stirred until the α,β-unsaturated ester iscompletely removed to produce the pyrrole ester compound of formula (1).In this reaction, TosMIC is added in an amount of 1 to 1.3 molarequivalent with respect to the compound of formula (2) and the base isadded in an amount fallen under the same range as mentioned in theprevious step of preparing the compound of formula (4). Then, thereaction solution is quenched with water and extracted with a suitableextracting solvent which is not miscible with water at temperature of 40to 90° C. (if a high yield is desired, 60 to 90° C. is preferable). Theorganic layer was separated and stirred at room temperature, and theformed precipitate is filtered to give the desired compound of formula(1) in a pure state. The solvent is not always required to remove beforecarrying out the extraction. But, in case of tetrahydrofuran ordimethoxyethane is used as the reaction solvent, since they are wellmiscible with water, it is required to be removed by distillation.Therefore, the increase of yield can be expected if the solvent isremoved in advance by distillation under reduced pressure before theextraction. As the extracting solvent for this purpose, toluene orn-butyl acetate can be preferably used. Particularly, whensodium-t-pentoxide is used as the base, since this base is well solublein the preferable extracting solvent toluene, the trouble to have to usean extracting solvent different from the reaction solvent may be saved.

The reaction for preparing the compound of formula (4) is proceeded attemperature ranging from −20 to 40° C., preferably 10 to 25° C. on asatisfactory level. Also, the process for producing the desired pyrroleester derivative of formula (1) from the compound of formula (4) thusobtained is suitably carried out at temperature ranging from 0 to 40° C.

Contrary to the prior arts, after the unsaturated ester compound offormula (4) is produced, it directly reacts with TosMIC without anyseparation or purification, in the present invention to afford thepyrrole ester. Thus, reduction of the waste solvent and enhancement ofthe efficiency of the process is obvious and provides great advantageparticularly when the process is applied on an industrial production.

The present invention will be more specifically explained in thefollowing examples. However, it should be understood that they areintended to illustrate the present invention but not in any manner tolimit the scope of the present invention.

EXAMPLE 1

1-Naphthaldehyde(35 g, 0.224 mol) and triethylphosphonoacetate(50 g,0.224 mol) were mixed under nitrogen atmosphere, 180 ml ofdimethoxyethane(DME) was added, and the resulting mixture was cooled to0° C. under a thorough stirring. To this solution was added slowlypotassium-t-butoxide(30 g, 1.2 molar equivalent) while maintainingreaction temperature below 20° C. After confirming the complete removalof 1-naphthaldehyde by HPLC, TosMIC(52.5 g, 1.2 molar equivalent) andpotassium-l-butoxide(32 g, 1.3 molar equivalent) were added slowly insequence maintaining the reaction temperature below 20° C. Afterconfirming the exhaustion of α,β-unsaturated ester by HPLC, 70 ml ofdistilled water was added and DME was removed therefrom by distillationunder reduced pressure. 200 ml of toluene was added to this concentrate.The mixture was warmed and extracted with 350 ml of distilled water. Theseparated organic layer was subjected to azeotropic distillation toremove the residual moisture. The concentrate was cooled with slowstirring to room temperature and the formed solid was filtered. Thefilter cake was washed twice with 30 ml of cold toluene, twice with 50ml of distilled water, and dried to give 37 g (HPLC Purity 95.2%, Yield61%) of the title compound as a white powder.

¹H NMR(CDCl₃, ppm) δ 8.65(1H, br, s), 7.80(3H, m), 7.59(1H, dd, J1=3.2Hz, J2=2.3 Hz), 7.41(4H, m), 6.79(1H, t, J=2.3 Hz), 3.91(2H, q, J=6.9Hz), 0.71(3H, t, J=6.9 Hz) 13C NMR(CDCl3, ppm) δ 165.2, 133.8, 133.51,133.50, 128.0, 127.5, 127.3, 126.7, 125.5, 125.4, 125.2, 124.7, 123.9,119.3, 115.9, 59.5, 13.7.

m.p.(not calibrated) 164-165° C.

EXAMPLE 2

1-Naphthaldehyde(28 g, 0.18 mol) and triethylphosphonoacetate (40.35 g,0.18 mol) were introduced into 500 mL round bottom flask and dilutedwith 180 ml of toluene. The reaction misture was cooled to about 0 to 5°C. and sodium-t-pentoxide (23.8 g, 0.216 mol) was added slowly in orderto maintain the reaction temperature below 20° C. After the addition wascompleted, the reaction mixture was stirred for 1 to 2 hours at roomtemperature and cooled again to 0 to 5° C. TosMIC(36.9 g, 0.189 mol) andsodium-t-pentoxide(23.8 g, 0.216 mol) were added slowly in sequencemaintaining the reaction temperature below 20° C. After the addition wascompleted, the reaction mixture was stirred for 3 to 6 hours at roomtemperature and 250 ml of distilled water was added. The resultingmixture was heated at about 70° C. and the organic layer was separated,washed once again with 250 ml of distilled water at the sametemperature. The separated organic layer was subjected to azeotropicdistillation to remove the residual moisture. Then, the concentrate wascooled to about 50° C. with slow stirring. After the crystal wasprecipitated, the reaction temperature was lowered to 0 to 5°C. andfurther stirred. The formed solid was filtered, washed twice with 30 mlof toluene and dried under nitrogen to give 29.6 g (HPLC Purity 96%PAR,Yield 62%) of the title compound as a white powder.

INDUSTRIAL APPLICABILITY

According to the process of the present invention, the pyrrole estercompounds of formula (1), key intermediates for preparing farnesyltransferase inhibitors, an anti-cancer agent, can be prepared with ahigh purity and yield on an industrial scale.

What is claimed is:
 1. A process for preparing a pyrrole esterderivative represented by the following formula (1):

in which R represents alkyl, allyl, or aryl, and R¹ representsC₁-C₄-alkyl, characterized by reacting an aldehyde compound representedby the following formula (2):

in which R is defined as previously described, with atrialkylphosphonoacetate represented by the following formula (3):

in which R¹ is defined as previously described, in an inert solvent inthe presence of an alkali metal alkoxide base in an amount of 1 to 1.5molar equivalent with respect to the compound of formula (2) to give anα,β-unsaturated ester compound represented by the following formula (4):

in which R and R¹ are defined as previously described, and subsequentlyby adding TosMJC and the same base as used in the previous step in anamount of 1 to 1.5 molar equivalent with respect to the compound offormula (2).
 2. The process of claim 1 wherein the alkali metal alkoxidebase is used in an amount of 1 to 1.3 molar equivalent with respect tothe compound of formula (2).
 3. The process of claim 1 or 2 wherein thealkali metal alkoxide base is sodium- or potassium-t-butoxide or-t-pentoxide.
 4. The process of claim 1 wherein the inert solvent istetrahydrofuran, dimethoxyethane, toluene or mixtures thereof.
 5. Theprocess of claim 1 wherein TosMIC is used in an amount of 1 to 1.3 molarequivalent with respect to the compound of formula (2).
 6. The processof claim 1 wherein the process for preparing the compound of formula (4)is carried out at temperature ranging from −20 to 40° C., and theprocess for preparing the compound of formula (1) is carried out attemperature ranging from 0 to 40° C.
 7. The process of claim 6 whereinthe process for preparing the compound of formula (4) is carried out attemperature ranging from 10 to 25° C.
 8. The process of claim 1 whereinthe compound of formula (1) is prepared and extracted with an organicsolvent further added, the organic layer is separated, and the compoundof formula (1) is recrystallized therefrom.
 9. The process of claim 8wherein the organic solvent is toluene or n-butyl acetate.
 10. Theprocess of claim 8 or 9 wherein the extraction is carried out attemperature ranging from 40 to 90° C.